Halogenophenyl-isoxazolyl-alkanoic acid derivatives

ABSTRACT

THIS DISCLOSURE RELATES TO HALOGENOPHENYL-ISOXAZOLEALKANOIC ACIDS AND DERIVATIVES WHICH POSSES ANTI-INFLAMMATORY, ANALGESIC AND ANTIPYRETIC ACTIVITY. A REPRESENTATIVE OF THE COMPOUNDS IS 5-(4-CHLOROPHENYL)ISOXAZOL-3YL-2-PROPIONIC ACID.

United States Patent cc 3,642,812 HALOGENOPHENYL-ISOXAZOLYL-ALKANOICACID DERIVATIVES Peter Fulton Southern, Macclesfield, England, assignorto {mpen'al Chemical Industries Limited, London, Engand No Drawing.Filed May 27, 1968, Ser. No. 732,034 Claims priority, application GreatBritain, June 15, 1967, 27,731/ 67 Int. Cl. C07d 85/22 US. Cl. 260-307 H5 Claims ABSTRACT OF THE DISCLOSURE This disclosure relates tohalogenophenyl-isoxazolealkanoic acids and derivatives which possesanti-inflammatory, analgesic and antipyretic activity. A representativeof the compounds is 5-(4-chlorophenyl)isoxazol-3- y1-2-propionic acid.

This invention relates to heterocyclic compounds, and more particularlyit relates to isoxazole derivatives which have anti-inflammatory,analgesic and antipyretic activity, to processes therefor, and topharmaceutical compositions containing said derivatives.

According to the invention we provide isoxazole derivatives of theformula:

11 Y-ii; z

wherein Y stands for a monohalogenophenyl or dihalogenophenyl radical,and Z stands for a group of the formula --CR R R wherein R and R whichmay be the same or different, stand for hydrogen or the methyl radical,and R stands for a group of the formula CO R or CONHR wherein R standsfor hydrogen or an alkyl radical of not more than 6 carbon atoms, or thephenyl or benzyl radical, and R stands for hydrogen or the amino (NHg)or hydroxy radical, and pharmaceutically-acceptable salts thereof.

It is to be understood that, in the isoxazole derivatives of thisinvention, when Y is linked to position 3 of the nucleus, Z is linked toposition 5, and, when Z is linked to position 3 of the nucleus, Y islinked to position 5.

The halogen substituents(s) which is or are present in Y may be selectedfrom fluorine, chlorine and bromine atoms.

As a suitable value for R when it stands for an alkyl radical of notmore than carbon atoms there may be mentioned, for example, the methyl,ethyl or n-butyl radical.

In the case where R stands for the carboxy radical (CO H), suitablesalts are salts with alkali or alkaline earth metals, for example sodiumor calcium salts, or aluminium or ammonium salts, or salts withpharmaceutically-acceptable organic bases.

Preferred compounds of this invention are 5-(4-chlorophenyl)isoxazol 3yl Z-propionic acid, 3-(2,4-dichlorophenyl)isoxazol 5 ylacetic acid,3-(4-chlorophenyl)- isoxazol 5 yl 2 isobutyric acid and its ammonium,sodium, calcium or aluminium salt, and ethyl 3-(4-chlorophenyl-isoxazol-5-yl-2-isobutyrate.

3,642,812 Patented Feb. 15, 1972 YEWCRIRKC 0211 wherein Y, R and R havethe meanings stated above, and R stands for an alkyl radical of not morethan 6 carbon atoms, which comprises reacting a compound of the formula:

wherein Y, R and R have the meanings stated above, and Cy stands for thecyano (CN) or carbamoyl (CONHg) radical, with a compound of the formulaR OH, wherein R has the meaning stated immediately above, under acidicconditions. The acidic conditions may be provided by the presence of aninorganic acid, for example sulphuric acid. A relatively small amount ofwater should be present. The reaction may be carried out in the presenceof an organic solvent, for example benzene, and it may be accelerated orcompleted by the application of heat.

According to a further feature of the invention we provide a process forthe manufacture of isoxazole derivatives of the formula:

wherein Y, R and R have the meanings stated above, which compriseshydrolysing a compound of the formula:

hydroxide, or an inorganic acid, for example sulphuric acid. Thehydrolysis is carried out in the presence of water, and an organicsolvent may optionally also be present. The reaction may be acceleratedor completed by the application of heat.

According to a further feature of the invention we provide a process forthe manufacture of isoxazole derivatives of the formula:

wherein Y and R have the meanings stated above and R stands for an alkylradical of not more than 6 carbon YJ F wherein Y and R have the meaningsstated above, and R has the meaning stated immediately above. It will bereadily understood that the methylation process can result in theintroduction of one methyl radical or of two methyl radicals. Themethylation may be carried out by the interaction of an alkali metalderivative, for example the sodium derivative of the appropriateisoxazole derivative with, for example, methyl iodide. The reaction maybe carried out in a diluent or solvent, for example ether, or liquidammonia, or a mixture thereof.

According to a further feature of the invention we provide a process forthe manufacture of amides of the formulaz wherein Y, R and R have themeanings stated above, which comprises hydrolysing the correspondingnitrile. The hydrolysis is carried out in the presence of water, and asa suitable hydrolytic agent there may be mentioned, for example, aninorganic acid, for example sulphuric acid, or an inorganic base, forexample an alkali metal hydroxide. The reaction may optionally becarried out in the presence of an organic solvent, for example ethanol,and it may optionally be accelerated or completed by the application ofheat.

According to a further feature of the invention we provide a process forthe manufacture of amides of the wherein Y, R R and R have the meaningsstated above, which comprises reacting a compound of the formula:

j-cn moom o wherein Y, R and R have the meanings stated above, and Rstands for a halogen atom or an alkoxy, benzyloxy or phenoxy radical, oran acid anhydride corresponding to the compound wherein R stands for ahalogen atom, with a compound of the formula NH R wherein R has themeaning stated above, provided that, when R stands for the aminoradical, R does not stand for a halogen atom. The reaction may becarried out in a diluent or solvent, for example water, and it mayoptionally be accelerated or completed by the application of heat.

According to a further feature of the invention we provide a process forthe manufacture of esters of the formula:

OR R .COgR

comprises esterifying the corresponding acid of the formula:

Y orumooin wherein Y, R and R have the meanings stated above, or an acidhalide or anhydride thereof.

The esterification may be carried out by reacting the carboxylic acidwith the compound of the formula R OH, wherein R has the meaning statedimmediately above, and an inorganic acid, for example sulphuric acid.Alternatively, the esterification may be carried out by reacting thecarboxylic acid halide, for example the acid chloride, or the carboxylicacid anhydride, with the compound of the formula R OH, wherein R has themeaning stated immediately above. In the case where an acid halide isused, an acid-binding agent, for example an alkali metal hydroxide orcarbonate, may optionally be present. In the case where R stands for themethyl or ethyl radical, the esterification may be carried out byreacting the carboxylic acid with diazomethane or diazoethanerespectively.

It is to be understood that the starting materials used in the processesof this invention may be obtained by generally known procedures.

According to a further feature of this invention we providepharmaceutical compositions comprising an isoxazole derivative of theformula:

wherein Y and Z have the meanings stated above, or apharmaceutically-acceptable salt thereof, and an inertpharmaceutically-acceptable diluent or carrier.

The pharmaceutical compositions may, for example, be in the form oftablets, pills, capsules, suppositiories, non-sterile aqueous ornon-aqueous solutions or suspensions, sterile injectable aqueous ornon-aqueous solutions or suspensions, creams, lotions, or ointments.These compositions may be obtained in conventional manner usingconventional excipients. The compositions may optionally contain, inaddition to the isoxazole derivative which characterises this invention,at least one known agent having anti-inflammatory and/or analgesicactivity, for example aspirin, paracetamol, codeine, chloroquine,phenylbutazone, oxyphenbutazone, indomethacin, mefenamic acid,fiufenamic acid, ibufenac, or an anti-inflammatory steroid, for exampleprednisolone. Those compositions intended for oral administration may,in addition, optionally contain at least one anti-cholinergic agent, forexample homatropine methyl bromide, and/or an antacid, for examplealuminium hydroxide. Those compositions designed for topical applicationmay, in addition, optionally contain a vasodilating agent, for exampletolazoline, or a vasoconstricting agent, for example adrenaline; a localanaesthetic, for example amethocaine, or a counter-irritant, for examplecapsicum; and/or at least one agent chosen from the following classes ofsubstances: antibacterial agents, which includes sulphonamides andantibiotics having antibacterial action, for example neomycin;antifungal agents, for example hydroxyquinoline; antihistaminic agents,for example promethazine; rubefacient agents, for example methylnicotinate; and uricosuric agents, for example probenecid.

The invention is illustrated but not limited by the following examplesin which the parts are by weight:

EXAMPLE 1 A mixture of 5 parts of 3-(4-chlorophenyl)isoxazol-S-ylacetonitrile, 20 parts of ethanol, 18 parts of concentrated sulphuricacid, and 1 part of water is heated at about 90 C. for hours. Thesolution is then poured into 200 parts of ice-water. The mixture isfiltered, and the solid residue is crystallised from aqueous ethanol togive ethyl 3-(4-chlorophenyl)isoxazol-S-lyacetate, M.P. 9394 C.

The nitrile used as starting material (M.P. 1l5116 C.; crystallised fromcyclohexane) may be obtained by means of a known general method.

EXAMPLE 2 A mixture of 1 part of ethyl3-(4-chlorophenyl)isoxazol-S-ylacetate and 12 parts of N-sodiumhydroxide solution is boiled for 10 minutes, and then cooled andacidified with concentrated hydrochloric acid. The resulting solid isfiltered oil? and crystallised from aqueous ethanol to give3-(4-chlorophenyl)isoxazol-S-ylacetic acid, M.P. 166167 C.

EXAMPLE 3 1 part of sodium is added to 100 parts of stirred liquidammonia containing a trace of ferric nitrate. When the formation ofsodamide is complete (shown by a colour change from blue to grey), asuspension of 11.1 parts of ethyl 3-(4-chlorophenyl)isoxazol-S-ylacetatein 60 parts of ether is added, and the mixture is stirred at -70 C. for30 minutes. A solution of 6 parts of methyl iodide in 30 parts of etheris added, and stirring at -70 C. is continued for 1% hours. 2.5 parts ofammonium chloride are then added, and the ammonia is allowed toevaporate at room temperature. 200 parts of ether are added to theresidue, and the resulting ethereal suspension is successively washedwith sodium bicarbonate solution, sodium bisulphate solution, and water.The organic solution is dried (anhydrous sodium sulphate) and thesolvent evaporated. The residual oil is separated by preparative-scalethin-layer chromatography on Kieselgel (Grade GF 254; available fromAnderman and Co. Ltd.; distributors for E. Merck Lab. Chemicals), usingcyclohexane-acetone (65:35 v./v.) as eluent, into ethyl3-(4-chlorophenyl) isoxazol-S-ylacetate (starting material), ethyl3-(4-chlorophenyl)isooxazole 5 yl-2-propionate, and ethyl 3 (4-chlorophenyl)isoxazol-S-yl-2-isobutyrate. Hydrolysis of the second andthird of these esters by the method described in Example 2 gives3-(4-chlorophenyl)isoxazol-S- yl-2-propionic acid, M.P. 144-145 C., and3-(4-chlorophenyl)isoxazol-S-yl-Z-isobutyric acid, M.P. 177-178" C.(crystallised from 50% aqueous ethanol).

EXAMPLE 4 A mixture of 1 part of 5-(4-chlorophenyl)isoxazol-3-ylacetouitrile, 1 part of potassium hydroxide, 2 parts of water, and 12parts of methanol is refluxed for 3 hours. The mixture is cooled, 120parts of water and 60 parts of chloroform are added, and the resultingmixture is well shaken. The mixture is then filtered, and the aqueousphase is separated from the filtrate. The aqueous phase is acidifiedwith concentrated hydrochloric acid, and the resulting mixture isfiltered to give, as solid residue, 5-(4-chlorophenyl)isoxazol-3-ylacetic acid, M.P. 164-165" C. (crystallisationfrom 50% aqueous ethanol).

The nitrile used as starting material (M.P. ISO-152 C.) may be obtainedin known general manner from the corresponding 3-chloromethyl compound.

In a similar manner, using the appropriate starting materials thefollowing compounds are obtained:

3-(4-bromophenyl)isoxazol-S-ylacetic acid, M.P.

158l59 C.; 3-(4-fluorophenyl)isoxazol-S-ylacetic acid, M.P.

15 0-15 1 C.; 3-(2,4-dichlorophenyl)isoxazol-S-ylacetic acid, M.P.

125-126 C.; 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyric acid, M.P.

. ing compounds are obtained as oils:

ethyl 3-(2,4-dichlorophenyl)isoxazol-S-ylacetate, N.M.R.

spectrum (1 values) s. 6.1., t. 8.7, p. 5.75;

ethyl 3-(4-chlorophenyl)isoxazol-S-yl-Z-isobutyrate,

N.M.R. spectlurn (7- values) s. 8.33, t. 8.8, q. 5.73;

methyl 3-(4-chlorophenyl)isoxazol 5 ylacetate) corresponding acid, M.P.166-167 C., obtained by hydrolysis with aqueous sodium hydroxide, seeExample 2); and

methyl 3 (2,4 dichlorophenyl)isoxazol 5 ylacetate,

N.M.R. spectrum (1- values), 5. 6.25, s. 6.08. (s=singlet; t.=triplet;q.=quartet).

EXAMPLE 6 The process described in Example 1 is repeated except that the3-(4-chlorophenyl)isoxazol-S-ylacetonitrile is replaced by 3 (4chlorophenyl)isoxazol-S-yl-Z-isobutyramide. In a similar manner there isobtained ethyl 3-(4- chlorophenyl)isoxazol-5-yl-2 iso'butyrate, N.M.R.spectrum (r values), s. 8.33, t. 8.8., q. 5.73.

EXAMPLE 7 The process described in Example 3 is repeated except that theethyl 3- (4-chlorophenyl)isoxazol-S-ylacetate is replaced by ethyl3-(2,4-dichlorophenyl)isoxazole-S-ylacetate. In a similar manner thereis obtained ethyl 3-(2,4-dichlorophenyl)isoxazol-5-yl-2-isobutyrate,N.M.R. spectrum (1- values), s. 8.33, q. 5.78, t. 8.75.

EXAMPLE 8 Hydrolysis of ethyl 3-(2,4-dichlorophenyl)isoxazol-S-yl-2-isobutyrate by the method described in Example 2 gives3-(2-,4-dichlorophenyl)isoxazol-S-yl 2 isobutyric acid, M.P. 109-110 C.

EXAMPLE 9 The method described in Example 4 is repeated, except that the5-(4-chlorophenyl)isoxazol-3-ylacetonitrile is replaced by theappropriate nitrile, and in similar manner there are obtained:

3- (12ig-dichlorophenyl)isoxazol-S-ylacetic acid, M.P. 138- C.; 3-(2chlorophenyl)isoxazol-S-ylacetic acid, M.P.

102 C.; and 5-(4 chlorophenyl)isoxazol-3-yl-2-propionic acid, M.P.

EXAMPLE l0 1 part of 3-(4-chlorophenyl)isoxazol-5-yl-acetonitrile isdissolved in 5 parts of concentrated sulphuric acid. After 2 days atroom temperature, the mixture is poured into water. The resulting solidis filtered OE and crystallised from methanol to give3-(4-chlorophenyl)isoxazol-S-ylacetamide, M.P. l91l92 C.

In a similar manner 3-(4-chlorophenyl)isoxazol-S-yl-Z- isobutyramide,M.P. -196 C. (decomposition), and3-(2,4-dichlorophenyl)isoxazol-S-ylacetamide, M.P. 14l- 142 C., areobtained from the corresponding nitriles.

EXAMPLE 11 1 part of 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyric acidis dissolved in 10 parts of aqueous ammonium hydroxide (specific gravity0.880). The solution is evaporated to dryness and the residual solid iswashed with ether to give ammonium 3-(4-chlorophenyl)isoxazol-S-yl-2-isobutyrate monohyrate, M.P. 168-169 C. (decomposition).

1 part of 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyric acid, 1.6 partsof N-sodium hydroxide solution and 5 parts of water are mixed, themixture is filtered and the filtrate is evaporated to dryness. Theresidual solid is crystallised from a mixture of ethanol and ether.There is thus obtained sodium 3-(4-chlorophenyl)isoxazol 5yl-2-isobutyrate dihydrate, M.P. 270 C. (decomposition).

8 parts of calcium chloride hexahydrate in solution in 300 parts ofwater are added to a solution of 23 parts of sodium3-(4-chlorophenyl)isoxazol-S-yl-2-isobutyrate in 500 parts of water. Thecalcium salt of 3-(4-chlorophenyl) isoxazol-5-yl-2-isobutyric acid isprecipitated and is collected by filtration, washed well with water anddried in vacuo at room temperature, M.P. over 200 C.

Replacement of the calcium chloride hexahydrate in the above experimentwith 9 parts of aluminum nitrate monohydrate gives the aluminum salt of3-(4-chlorophenyl)-isoxazol-5-yl-2-isobutyric acid, M.P. over 200 C.

EXAMPLE 12 1 part of 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyrylchloride is added slowly to parts of ammonium hydroxide (specificgravity 0.880) at 0 to 10 C. parts of water are added and the mixture isfiltered. There is thus obtained3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyramide, M.P. 190-l91 C.

EXAMPLE l3 1 part of 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyrylchloride and 3 parts of dry ethanol are refluxed together for minutes.The mixture is evaporated in vacuo to dryness, giving ethyl3-(4-chlorophenyl)-isoxazol-5-yl-2-isobutyrate, N.M.R. spectrum (1-values), s. 8.33, t. 8.8, q. 5.73.

Similarly, using n-butanol in place of ethanol, there is obtainedn-butyl 3 (4-chlorophenyl)isoxazol-S-yl-Z-isobutyrate, N.M.R. spectrum(7' values), s. 8.33, t. 5.88, and a complexity of peaks at 8.25 to9.25.

EXAMPLE 14 4 parts of 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyric acidand 1 part of diazomethane in ether are mixed at 0 C., and stood at roomtemperature until evolution of nitrogen ceases. Evaporation to drynessyields methyl 3-(4- chlorophenyl)isoxazol-5-yl-2 isobutyrate, N.M.R.spectrum (7 values), s. 8.33 and 6.28.

EXAMPLE 15 1 part of 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyrylchloride is added dropwise with vigorous agitation to a solution of 1part of phenol in 10 parts of 10% aqueous sodium hydroxide. After 2hours, the solid is filtered off and crystallised from aqueous ethanolto give phenyl 3-(4- chlorophenyl)isoxazol-S-yl-Z-isobutyrate, M.P.105-106 C.

EXAMPLE l6 1 part of 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyric acid,1.3 part of benzenesulphonyl chloride, and parts of dry pyridine aremixed and stirred at 0 C. for 1 hour. There is thus obtained a solutioncomprising 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyric acid anhydride(M.P. 1l2-114 C.) in pyridine. 0.5 part of benzyl alcohol is added tothis solution, and the mixture is stirred at room temperature for 24hours. The mixture is poured into water, the resulting mixture isfiltered, and the solid residue is crystallised from aqueous ethanol.There is thus obtained benzyl 3-(4-chlorophenyl)isoxazol 5yl-2-isobutyrate, M.P. 72-73" C.

EXAMPLE 17 1 part of methyl 3-(2,4-dichlorophenyl)isoxazol-5-yl' acetateand 10 parts of aqueous ammonium hydroxide (specific gravity 0.880) arestirred together at room temperature for 3 days. 30 parts of water arethen added,

the mixture is filtered, and the solid residue is crystallised frombenzene. There is thus obtained 3-(2,4-dichlorophenyl)isoxazol-S-ylacetamide, M.P. l4l-l42 C.

EXAMPLE 18 10 parts of methyl 3 (2,4-dichlorophenyl)-isoxazol-S-ylacetate are added over 15 minutes to 3 parts of hydrazine hydrate.After heating on a steam bath for 8 hours, the solid is collected byfiltration, washed with water, and then crystallised from parts ofethanol to give 3 (2,4 dichlorophenyl)isoxazole-5-ylacethy' drazide,M.P. 147.5148 C.

EXAMPLE 19 0.15 part of sodium is dissolved in 16 parts of dry methanol.0.25 part of hydroxylamine hydrochloride and 1 part of methyl 3 (2,4dichlorophenyl)isoxazole-S- ylacetate are added to the solution. Themixture is kept at room temperature for 24 hours. 50 parts of water areadded, and the resulting mixture is filtered to give 3 (2,4dichlorophenyl)isoxazol 5 ylacethydroxamic acid, M.P. l60-161 C.

EXAMPLE 20 A mixture of parts of 5-(4-chlorophenyl)isoxazol-3-yl-2-propionic acid and 300 parts of maize starch is granulated with asufiicient quantity of 10% w./v. starch paste. The granules are passedthrough a 20-mesh screen and are dried at a temperature not exceeding 50C. The dried granules are blended into 4 parts of magnesium stearate,and compressed into tablets which may contain from 50 to 250 mg. ofactive ingredient. There are thus obtained tablets suitable for oral usefor therapeutic purposes.

Instead of 100 parts of 5-(4-chlorophenyl)isoxazol- 3-yl-2-propionicacid there may be used 100 parts of 3 (2,4dichlorophenyl)isoxazol-S-ylacetic acid or 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyric acid.

EXAMPLE 21 50 parts of micronised 3-(2,4-dichlorophenyl)isoxazol-5-ylacetic acid are mixed with parts of lactose and 35 parts of 10%w./v. aqueous gelatine solution, and the mixture is granulated. 24.5parts of maize starch are mixed with the granules, and 2 parts ofmagnesium stearate are then added. The mixture is compressed intotablets containing 50 mg. of active ingredient. There are thus obtainedtablets which are suitable for oral administration for therapeuticpurposes.

EXAMPLE 22 5 parts of 3-(4-chlorophenyl)isoxazol-5-yl-2-isobutyric acidare added to a stirred mixture of 9 parts of liquid paraffin and 86parts of white soft paraffin heated at 65 C. Stirring is continued untilthe mixture is cool, and there is thus obtained an ointment suitable fortopical application for therapeutic purposes.

The isoxazole derivatives of this invention are active in the followingprocedure which is standard in the art for testing for anti-inflammatoryactivity (Newbold, Brit. J. Pharmacol. Chemotherap, 1963, 21, 127-136).

Adjuvant induced arthritis in rats When 0.05 ml. of a fine suspensioncontaining 5 mg./ ml. of dead tubercle bacilli in liquid paraffin isinjected into the foot-pad of a rat, a primary swelling is produced.This swelling increases in size for three days, and then diminishesslightly until the seventh day, when further swelling occurs. Ten daysafter the injection, inflamed lesions (Which are called secondarylesions) appear in areas of the body which are remote from the actualsite of injection; particularly on the joints of the forepaws, hind-pawsand tail. Little further swelling of the feet or joints occurs after thethirteenth day (after the injection). These secondary lesions areconsidered to have arisen as a result of an immunological reactioninvolving constituents of the dead tubercle bacilli which becamedisseminated after injection.

The isoxazole derivatives of this invention have been tested foranti-inflammatory properties as follows:

Each rat in a group of 3 male rats (average weight ca. 200 g.) was dosedorally with the test compound (as an aqueous suspension), and, on theday after dosing, an injection of dead tubercle bacilli was given asabove. There as one control group of 3 rats (which received deadtubercle bacilli but no test compound) for every 5 groups of ratsreceiving test compounds. The test compound was then dosed orally eachday until the thirteenth day after the injection of the dead tuberclebacilli. The

thickness of the injected foot was measured 3 days after 4 injection and13 days after injection. The results were expressed as the percentageinhibition of the increase in thickness of the injected feet of thetreated rats. The results obtained with a representative selection ofthe said isoxazole derivatives are shown in the following table (in thecases where the word Toxic appears, all the rats died before thethirteenth day after the injection.

u 2. J. o 1

Percent inhibition Substituent at Substitucnt at Dose, Day Day position3 position 5 Ing./kg. 13 3 4.0LPhenyl CH2.COOH 100 62 32 4.01.]?henylCH(Me).COOH g8 50 58 50 4.Cl.Phenyl CMez.COOH 38 48 33 100 74 184.Cl.Phenyl CH2.CONH2 50 57 38 4..Br.Phenyl CH2.COO 50 53 29 4.Br.PhenylOM92 COH 100 52 44 4.F.Phenyl C 50 2 4.F.Pheny1 CMez.COOH 100 47 4g2,4.diCLPhenyl orncoon 3 h 1 a 0H 4.01.1 en 5 5 CH2 CO Y 50 51 36 100Toxic CH(Me).CO0H 4.01.1heny1 g(? 57 CMe .CO0H 4.C1.Phenyl g CH(Me).CO0H4.C1.Phenyl 40 2.Cl. Phenyl CH2 COOH CMez.COOEt 53 4 CMez.COOBu( 51 2,4CMez.CO OH.-. 51 4.C1.Phenyl CMB2.CONH2-. 55 4.Cl.Phenyl CMeaCO OMe 434.01 PhenyL- CMez.CO0 CH2Ph 55 4.Cl.Phenyl CMez.COOPh- 52 2,4.0lz.PhenylCHZCONHz--- 59 2,4.Clz.Phenyl CHZCONHNH 50 The above results prove thatthe compounds in question exhibit anti-inflammatory activity in the rat,inasmuch as the compounds partially prevent the development ofinflammation on Day 3 and Day 13. Moreover, toxicity data indicates thatthe compounds are not undesirably toxic at useful dosage levels.

It is well known and accepted in the art that nonsteroidalanti-inflammatory compounds exhibit analgesic and antipyretic activity.The compounds of this invention are nonsteroidal and they exhibitanti-inflammatory activity, as evidenced by the above results.Accordingly, it is rea sonable to conclude that the isoxazolederivatives of this invention possess analgesic and antipyreticactivity.

The compounds of the invention are generically useful in the treatmentof Warm-blooded animals (including mammals) and, for this purpose, -werecommend that said compounds be administered orally, for example intablet or capsule form, and that the daily dosage be in the range ofabout 2 mg. to 50 mg. per kg. of host. In particular, when one of thesaid compounds is used in the treatment of man, we recommend that it beadministered orally, for example in tablet or capsule form, at a totaldaily dose of 100 mg. to 3,000 mg. of said compound per kg. man.

What we claim is: 1. A compound selected from the group consisting ofisoxazole derivatives of the formula:

Y is a member selected from the group consisting of monohalogenophenyland dihalogenophenyl;

R and R are members selected from the group consisting of hydrogen andmethyl; and R is a member selected from the group consisting of CO R and-CONI-IR wherein R is a member selected from the group consisting ofhydrogen, alkyl of not more than 6 carbon atoms, phenyl and benzyl; and

R is a member selected from the group consisting of hydrogen, amino andhydroxy; and pharmaceutically-acceptable salts thereof.

2. A compound as claimed in claim 1 which is 5-(4-chlorophenyl)isoxazol-3-yl-2-propionic acid.

3. A compound as claimed in claim 1 which is 3-(2,4-dichlorophenyl)isoxazol-S-ylacetic acid.

4. A compound as claimed in claim 1 which is a member selected from thegroup consisting of 3-(4-chlorophenyl)isoxazol-5-y1-2-isobutyric acidand its ammonium, sodium, calcium and aluminium salts.

5. A compound as claimed in claim 1 which is ethyl3-(4-ch1orophenyl)isoxazol-S-yl-Z-isobutyrate.

6. As a pharmaceutical composition of matter, a com pound in claim 1 inadmixture with a major amount of an inert, pharmaceutically-acceptablediluent.

References Cited UNITED STATES PATENTS 3,239,533 3/1966 Kano et al260-607 ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner U.S.Cl. X.R. 424-272

